The LPS-unresponsive C3H/HeJ mouse strain has been utilized to help elucidate the mechanism of action of bacterial endotoxin (LPS). Previous studies revealed that C3H/HeJ mice possessed a defect in LPS responsiveness that was intrinsic to their B lymphocytes. We have now found that their macrophages are also intrinsically unresponsive to LPS. Genetic analysis revealed that LPS-responsiveness of macrophages was controlled by a single, autosomal dominant gene that was probably identical to the gene controlling B-cell LPS-responsiveness. CBA/N mice possess an X-linked defect in B-cell maturation. We found that these mice exhibited abnormal B-cell responses to LPS but that their macrophage LPS responses were normal. Since CBA/N mice are normally sensitive to LPS, these findings strengthen the proposed role of macrophages in mediating endotoxicity. In addition, LPS-stimulated C3H/HeJ macrophages do not release prostaglandins in vitro in contrast to normal macrophages, suggesting that LPS-induced prostaglandin release by macrophages may be one of the initiating events in endotoxicity. BIBLIOGRAPHIC REFERENCES: Rosenstreich, D.L. and Blumenthal, R.: Ionophorous activity and murine B cell mitogens. J. Immunol. 118: 129-136, 1977. Kabir, S. and Rosenstreich, D.L.: The binding of bacterial endotoxin to murine spleen lymphocytes. Infect. and Immunity, 15: 156-164, 1977.